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Regulation of KRAS protein expression by miR-544a and KRAS-LCS6 polymorphism in wild-type KRAS sporadic colon adenocarcinoma

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Abstract

Colorectal carcinoma (CRC) results from the accumulation of genetic mutations and alterations in signaling pathways. KRAS is mutated in 40% of CRC cases and is involved in increased tumor cells proliferation and survival. Although KRAS mutations are a dominant event in CRC tumorigenesis, increased wild-type KRAS expression has a similar effect on accelerated tumor growth. In this study, we investigated the KRAS status in correlation with clinicopathological features in sporadic CRC and more importantly the role of let-7a-5p and miR-544a-3p in the regulation of wild-type KRAS protein expression in the tumor center (T1) and invasive tumor front (T2). Analysis showed that 39.1% of tumor samples had KRAS mutations. In wild-type KRAS tumors, 62.0% were positive for KRAS protein expression and there was a higher percentage of KRAS-positive tumor cells and a higher intensity of immunohistochemical reaction in T2 than in T1 samples. This could not be attributed to differences in KRAS mRNA levels, suggesting regulation via miR-544a-3p expression which was significantly decreased in T2 samples. Furthermore, we demonstrated that tumor samples carrying the KRAS-LCS6 variant allele had significantly higher protein expression of the wild-type KRAS. Our results suggest the role of the KRAS-LCS6 polymorphism and miR-544a-3p expression in the regulation of wild-type KRAS protein expression in sporadic CRC.

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Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Funding

The present study was supported by the Croatian Science Foundation (Grant number HRZZ-IP-2016-06-1430).

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Author notes

  1. Sonja Marinović and Anita Škrtić contributed equally to this work.

Authors and Affiliations

  1. Division of Molecular Medicine, Laboratory for Personalized Medicine, Ruđer Bošković Institute, Zagreb, Croatia

    Sonja Marinović, Tina Catela Ivković & Sanja Kapitanović

  2. Department of Pathology, Clinical Hospital Merkur, Zagreb, Croatia

    Anita Škrtić

  3. Department of Surgery, Clinical Hospital Merkur, Zagreb, Croatia

    Mirko Poljak

  4. Central European Institute of Technology, Masaryk University, Brno, Czech Republic

    Tina Catela Ivković

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  1. Sonja Marinović
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  2. Anita Škrtić
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Contributions

SM: investigation, formal analysis, and writing—original draft, AŠ: resources, formal analysis, and visualization, TCI: investigation and formal analysis, MP: resources, SK: conceptualization, funding acquisition, and writing—reviewing and editing.

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Correspondence to Sanja Kapitanović.

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The authors have no relevant financial or non-financial interests to disclose.

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Written informed consent was obtained from all patients included in the study. The study was approved by the ethics committee of Merkur Clinical Hospital, Zagreb and Medical School, University of Zagreb, and was performed under the ethical standards of the Helsinki Declaration.

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Marinović, S., Škrtić, A., Catela Ivković, T. et al. Regulation of KRAS protein expression by miR-544a and KRAS-LCS6 polymorphism in wild-type KRAS sporadic colon adenocarcinoma. Human Cell 34, 1455–1465 (2021). https://doi.org/10.1007/s13577-021-00576-2

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